Project Summary Traumatic brain injury (TBI) afflicts many men and women in both military and civilian populations. The early post-TBI period is characterized by neuroinflammation and oxidative stress followed by neurobehavioral changes that include sleep disturbances, neuroendocrine dysfunction, cognitive impairments, and behavioral impairments that include higher anxiety and depression, increased stress sensitivity, anhedonia, impulse control deficits, and higher pain sensitivity. All of these behavioral symptoms can promote escalated alcohol drinking in humans in an attempt to mitigate their symptoms, and this can eventually increase the likelihood of an alcohol use disorder (AUD) diagnosis. The neurobiological mechanisms underlying post-TBI escalation of alcohol drinking are not known. Critical from a healthcare burden perspective, our lab and others have shown that post-TBI alcohol exposure impairs recovery of neurobehavioral function, exacerbates gliosis, and prevents resolution of neuroinflammation. Preliminary data show increased glutamatergic signaling and synaptic hyperexcitability at the site of injury and in the basolateral amygdala, which we believe underlies previously observed post-TBI escalation of alcohol drinking and increased motivation to obtain alcohol. Moreover, our data show that a single post-injury administration of JZL184, a monoacylglycerol lipase (MAGL) inhibitor that prevents endocannabinoid degradation, attenuates neuroinflammation and improves neurobehavioral recovery post-TBI. In addition, JZL184 rescues excessive glutamatergic signaling and neuronal hyperexcitability at site of injury, and reduces motivation to obtain alcohol. Proposed studies will use male and female rats to test the hypothesis that synaptic hyperexcitability is associated with post-TBI increases in anxiety-like behavior and alcohol drinking. We predict that pharmacological (i.e., JZL184) and non-pharmacological (i.e., abstinence) therapeutic interventions will reduce post-TBI escalation of alcohol drinking and prevent post-TBI synaptic hyperexcitability in alcohol drinkers. Studies proposed will use an integrated experimental approach (behavior, immunohistochemistry, biochemistry, electrophysiology, pharmacology, and chemogenetics). An interdisciplinary team of investigators with established records of accomplishment on studies of TBI and inflammatory responses to alcohol (Molina); animal models of alcohol self-administration, dependence, and behavioral pharmacology (Gilpin); biochemical signaling mechanisms of alcohol dependence (Edwards); and electrophysiological investigations of neuronal synaptic circuitry (Middleton) will conduct them. The overarching goal of this project is to determine whether preventing pathological post-TBI synaptic plasticity in amygdala prevents post-TBI escalation of alcohol drinking and improves post-TBI outcomes. Studies will be supported by the outstanding scientific environment and Core analytical facilities supported by the NIAAA-funded LSUHSC Comprehensive Alcohol Research Center.